Technical Field
Provided herein are antisense oligonucleotides, compositions comprising antisense oligonucleotides, and methods for the use of antisense oligonucleotides in manipulating translation.
Description of the Related Art
The human genome is composed of approximately 28,000 genes from which approximately 150,000 proteins are derived. The mechanisms by which multiple proteins can be generated from a single gene include alternate use of promoters, splice sites, polyadenylation sites, translation initiation codons, RNA editing and selenocysteine insertion. In the case of alternate translation initiation start sites, a potential family of related proteins can be produced from a single transcript which can result in qualitative and quantitative differences in the expressed proteins. The biological significance of alternate translation start sites is determined by the differences in the peptide segment that is not shared by the two or more proteins derived from the same gene. The activity of one or more of such proteins may be associated with a disease.
In one example, the p53 tumor protein is translated as different isoforms with distinct biological effects. The p53 tumour suppressor gene encodes a transcription factor that is commonly inactivated in human cancer. In response to many forms of stress including DNA damage and replicative stress, p53 can regulate the expression of genes that block cell cycle progression or promote apoptosis, enabling p53 to eliminate premalignant cells that could otherwise give rise to cancer. As a result, much effort is directed at reconstituting or reactivating p53 expression in tumour cells that have undergone loss or missense mutation in p53.
p53, however, can also promote the repair and survival of damaged cells through a large number of mechanisms (see Kim et al., 2009; and Vousden and Prives, 2009). The dual function of p53 in promoting death or survival raises questions regarding the determinants that govern the cellular response to p53. The dual function of p53 must also be considered in the treatment of tumours that retain wild-type and even mutant p53 alleles.
Moreover, many isoforms of p53 exist, some of which may possess novel and unanticipated functions (see Harms and Chen, 2006). For instance, mouse p44 has both positive and negative effects on the transcription regulatory functions of p53 depending on the specific target gene (see Maier et al., 2004) and even though p53β/γ lacks the oligomerization domain and was reported to lack transcriptional activity, it retains the ability to bind certain p53-response elements on DNA (see Bourdon et al., 2005). It would be advantageous to interfere with p53-mediated survival in certain types of cancers, and to minimize induction of p53 isoforms having unanticipated activities
There exists a need for compositions and methods for modulating the translation of protein isoforms associated with alternate translation initiation start sites, particularly in relation to disease-associated protein isoforms. The present invention meets this need and offers other related advantages.